The NCRI AML14 Trial was devised for patients aged over 60 years with de novo or secondary AML or high risk MDS (defined as >10% blasts). There was a non-intensive option which compared Low Dose Ara-C vs Hydroxyurea each with or without All-Trans Retinoic Acid which has been reported previously (

Burnett et al Blood 2004: 249a
), and an intensive approach which we now report. This compared two dose levels of Daunorubicin (50mg/m2 vs 35mg/m2) and Ara-C (200mg/m2 vs 400mg/m2) within a Daunorubicin/Ara-C (3+10) followed by (3+8) schedule. After a 3rd course (MidAC: Mitoxantrone/Ara-C), patients were randomised to receive or not a 4th course (ICE: Idarubicin/Ara-C/Etoposide). In addition some patients (n=200) were randomised to receive PSC-833 in addition to Dauno 35. The results of this randomisation have been reported previously (Burnett et al Blood 2003614a).

A total of 1273 patients entered the trial between December 1998 and closure in May 2005, from 136 centres. Follow-up is complete to 1st April 2005, with median follow-up of 33 months. The median age was 67 (range 44-88). Cytogenetics were known for 67% of patients: of these, 3% had favourable, 74% intermediate and 23% adverse cytogenetics. 72% had de novo AML, 17% had secondary disease and 11% had high risk MDS. The overall CR rate was 62% and the Relapse Risk (RR), Disease Free Survival (DFS), and Overall Survival (OS) were 84%, 13%, and 13% at 5 years. 896 patients were randomised to D50 vs D35. No significant differences were found in CR (63% vs 64% OR 1.04 (95% CI 0.78–1.37)), RR (84% vs 85% OR 0.85 (95%CI 0.65–1.06)), DFS 14% vs 13% OR 0.86 (95% CI 0.70–1.06)), or OS (15% vs 13% OR 0.92, 95% CI (0.72–1.08)). Likewise, there were no significant differences in outcome for the 1264 patients randomised to Ara-C 200 vs 400: CR (62% vs 62% OR 1.00 (95% CI 0.80–1.27)), RR (84% vs 85% OR 1.14 (95% CI 0.95–1.37)), DFS (13% vs13% OR 1.14 (95% CI 0.96–1.14)) or OS (13% vs 12% OR 1.00 (95%CI 0.87–1.14)). In the 255 patients randomised to a total of 4 vs 3 courses the RR (83% vs 76% OR 0.90 95%CI 0.66–1.24), DFS (16% vs 18% OR 0.94 95% CI 0.69–1.28) and OS (23% vs 22% OR 1.05, 95% CI 0.75–1.47) were not significantly different.

From this preliminary analysis we conclude that there is no difference between a reduced dose of Daunorubicin (35mg/m2) compared with standard dose, or between enhanced Ara-C dose (400mg/m2) or standard dose and the confidence intervals are consistent with at most a moderate difference in treatment effect. We found no benefit for giving more than 3 courses of total treatment to patients in this age group, although the confidence intervals here do not rule out moderate, but potentially meaningful differences.

Topics:
blast cells, cytarabine, daunorubicin, duration of treatment, etoposide, follow-up, hydroxyurea, idarubicin, leukemia, secondary acute, milk-alkali syndrome

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2005, The American Society of Hematology
2005
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